1. Field of the Invention
This invention relates to apparatus and method for mass transfer involving biological/pharmaceutical media, as materials to or from which mass is being transferred.
2. Description of the Related Art
Mass transfer operations are used in numerous application areas for the concentration, purification, and separation of various biological/pharmaceutical media. Examples include: removal of sodium salts from pharmaceutical compositions to provide low-sodium products for human consumption; growth of cell cultures for research; removal of uric acid, creatinine, and various undesired electrolytes from blood, via hemodialysis; and the production and harvesting of viruses for vaccine production, or other intracellular products or secreted biologicals, such as immunoglobins, interleukens, interferons, clotting factors, and the like.
In applications of the above-described type, it is frequency practice to utilize a mass transfer chamber in which a mass transfer surface element is disposed which defines passages on its respective sides, in which the biological/pharmaceutical medium is disposed on one side of the element, and the medium to which or from which mass transfer is to be effected, is disposed on the opposite side of the element. The respective media are contacted in their separate passages via the mass transfer element with one another, e.g., in countercurrent flow to one another, or with one of the materials retained in batch fashion in its passage(s) while the other material flows past the mass transfer element on its opposite side, to effect diffusional and/or osmolytic mass transfer.
A particular problem which has arisen in the operation of such systems is their tendency to experience fouling of the mass transfer element after a period of operation. As an illustration, in systems where cell media are grown by flow of a nutrient medium on one side of the mass transfer element, for diffusional transfer of nutrient species to a microbial culture on the opposite side of the element, the system after a period of operation experiences preferential areas of cell growth which inhibit further mass transfer. In other instances, where proteins are secreted by cellular media and subsequently transfused across the mass transfer element to a recipient medium, proteinaceous species deposit on the surfaces of the mass transfer element and create a physical barrier to continue diffusional transfer of the desired products.
These problems are particularly acute in mass transfer surface elements such as hollow fiber bundles, of the type wherein a plurality of interior passages accommodate flow of a first medium therethrough, while a second medium is contained in or flowed through the interstitial passages provided between adjacent hollow fibers in the bundle. Such hollow fiber mass transfer elements may have discrete fiber open area (inner diameter) dimensions on the order from about 0.25-1 mm, with pores in the mass transfer surface on the order of about 0.2 micron in diameter. Due to the small dimensions involved, these mass transfer elements are highly suspectible in operation to clogging and consequential reduction in the extent and rate of mass transfer.
In addition to hollow fiber membrane modules of the above-described type, sponge-like chambers or honeycomb-like modules are variously employed. The hollow fiber membrane modules, however, are currently the most widely employed in cell growth applications, blood dialysis, and various other application areas.
In the specific area of nutrient mass transfer cell growth systems, a severe problem in the use of the aforementioned mass transfer chambers is the formation of micro-environments within the chambers. Such micro-environments are characterized by poor growth rates, poor longevity of the microbial population, and most notably areas of active growth within the chamber compared to other areas therein apparently supporting little or no growth.
In these chambers, all cell types, both procaryotic and eucaryotic, when grown as suspension cultures or anchored to a perfusion matrix in the mass transfer chamber, have been observed to grow far more luxuriantly at one end of the chamber than the other. Neither agitation, as by the use of shaker apparatus, nor turning of the chamber to manually manipulate its orientation, has resolved the problem of formation of these inappropriate micro-environments.
It has been observed that the preferential growth areas are normally adjacent to the inlet flow of nutrient source to the mass transfer chamber, and that such active growth at the inlet terminal effectively causes the following problems: (1) poor utilization of total potential volume of the chamber for culturing; (2) poor diffusion of nutrient components within these regions of high cell growth; and (3) undesirable accumulation of metabolic wastes in and around the area of high cell growth, which may physically plague the desired nutrient mass transfer operation, particularly if such wastes deposit on the surfaces of the mass transfer element.
Accordingly, it is an object of the present invention to provide an improved apparatus and method for effecting mass transfer operations involving biological/pharmaceutical media, in which the reduction of mass transfer attendant to prolonged operation is minimized.
It is another object of the invention to provide a system comprising a mass transfer chamber in which longitudinal decrease of mass transfer efficiency with prolonged operation, due to fouling of mass transfer surfaces, is minimized.
It is another object of the invention to provide improved apparatus and method for growing cells, in which undesireable formation of micro-environments, and areas of preferential growth, may be substantially avoided.
Other objects and advantages of the invention will be more fully apparent from the ensuing disclosure and appended claims.